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Unraveling transcriptomic and functional changes to immune sensing neuronal ganglia in response to allergy and bacteria

Award Number: R21AI159221
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Allergies affect millions of Americans and are exacerbated by bacterial infection. Despite mainstay therapies that suppress immune responses to allergy or bacteria, these health issues continue to persist. An unexplored target for new therapies lies with neural surveillance and regulation of immunity. However, this neural influence is poorly understood and seemingly paradoxical: immune responses are exacerbated in allergy, but in response to bacterial infection, the neural response reduces inflammation. How might this happen? One possibility is that the peripheral neural-immune sensing apparatus might be altered by such factors as immunoglobulin profiles, and gender, implying the participation of sex hormones. We hypothesize that such variables affect the transcriptome and thereby the excitability of the vagus and carotid bodies. Studies in AIM 1 will use single-cell RNAseq analysis of vagal and carotid body ganglia from male and female mice with asthma, pneumonia to identify how these nerves are changed in response to each condition. Then, we will assess nerve activity in response to immunoglobulin stimuli of each ganglia using state-of-the-art electrophysiological recording techniques. This project will reveal which neural cluster (vagus vs. carotid body) is the predominant sensory ganglia involved in regulating allergic vs. bacterial immune responses and how sex may affect neuro- immune signalling. Studies in AIM 2 will utilize DTR (diphtheria toxin receptor) technology in mice to selectively ablate cells where DTR expression is driven by TRPV1 (transient receptor potential vanilloid 1) or TH (tyrosine hydroxylase). Use of these transgenic mice will allow ablation of either vagal (TRPV1-DTR) or carotid body (TH- DTR) centers by direct neural microinjection of diphtheria toxin (DTX) into vagal or carotid body ganglia using saline injections as control. We will then expose mice to either allergen or bacterial infections. DTX injections will selectively abolish neuronal function and reveal which ganglion is the predominant neuro-immune sensor in the specified condition in male and female mice. These data will: 1) identify how the response to allergic or bacterial stimuli alters receptor gene expression in order to identify the phenotypic switch from anti- to pro-inflammatory neural-immune signalling; 2) establish a model and sex differences that will set the stage for further investigation involving targeted knockdown within neuro-immune sensing ganglia to discern function; 3) validate our models and methods for future investigations into the role of neural-immune sensing in disease states.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $195,630 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/6/2023	NON-COMPETING CONTINUATION	$195,630
														Subtotal = $195,630

Issue Date FY: 2022 ( Subtotal = $242,678 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	5/4/2022	NEW	$242,678
														Subtotal = $242,678

Grand Total All Awards = $438,308

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Unraveling transcriptomic and functional changes to immune sensing neuronal ganglia in response to allergy and bacteria

Award Number: R21AI159221

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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